Mitochondrial Cytopathy        Prof. Surender K Yachha Department of Pediatric Gastroenterology          SGPGIMS, Lucknow
Mitochondria: “Powerhouse” of the cell                                 FAOD                                  RCD
Defect
Mitochondrial diseases           High energy           dependency               In disease Mutant mitochondrial DNA >>> no...
Mitochondria                   and            respiratory chain                                 Dependence on Aerobic path...
80% calories (during fasting)       24 hr: adults       12 hr: infants           Most affected
ConsequencesGlycolysis                                      Hypoglycemia    Not metabolised    Respiratory    Try to spare...
Disorders inMitochondrial Hepatopathy1. Fatty Acid Oxidation Defects  2. Respiratory Chain Defects
“The Masquerader Of All Diseases”        Highly Deceptive !
Why do we struggleto identify this disease ?        Mitochondrial          Diseases
Settings to predict this disease
Settings in GI practice
107 patients              FAOD                                  74% 30%      31%            13%            16%         10%...
24%8%    FAOD & RCD -    Clinical features8%3%8%8%20%      Lee ,Sokol Semin Liver Dis5%           2007;27:259–273.
Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
FAOD                           ImportanceShort Chain                     Not much of a problemDoes it really exist??     ...
Long Chain Hydroxy Acyl CoA Dehydrogenase Def.                  (LCHADD) Early onset: severe         Hypertrophic cardiomy...
Very Long and Long ChainHydroxy Acyl CoA Dehydrogenase Def.      (VLCHADD and LCHADD)           J Inherit Metab Dis (2010)...
Biochemical differentiation        Acidosis         Urine      Blood sugar Serum Serum                        ketones     ...
Fatty Acid Oxidation Defects                  Screening                            Definitive              (available in I...
Respiratory Chain Defects               involving Liver  Disorder        Onset             Disorder             OnsetNeona...
Respiratory Chain Defects involving LiverNeonate   Infancy   Childhood    Adult
Respiratory Chain Defects
Definitive                       Sample                 Availability     Tests                                            ...
Treatment  Lee ,Sokol Semin Liver Dis 2007;27:259–273
Role of Carnitine    Lee ,Sokol Semin Liver Dis 2007;27:259–273
14 mitochondrial hepatopathy ahmedabad-july-2012
14 mitochondrial hepatopathy ahmedabad-july-2012
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14 mitochondrial hepatopathy ahmedabad-july-2012

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14 mitochondrial hepatopathy ahmedabad-july-2012

  1. 1. Mitochondrial Cytopathy Prof. Surender K Yachha Department of Pediatric Gastroenterology SGPGIMS, Lucknow
  2. 2. Mitochondria: “Powerhouse” of the cell FAOD RCD
  3. 3. Defect
  4. 4. Mitochondrial diseases High energy dependency In disease Mutant mitochondrial DNA >>> normal DNA and consequentially shifting proportions Shift from one clinical phenotype to another with age
  5. 5. Mitochondria and respiratory chain Dependence on Aerobic pathway for ATP Anaerobic pathway(oxidative phosphorylation) (glycolysis) Increase lactate 38 ATP Only 2 ATP
  6. 6. 80% calories (during fasting) 24 hr: adults 12 hr: infants Most affected
  7. 7. ConsequencesGlycolysis Hypoglycemia Not metabolised Respiratory Try to spare in FAOD chain defects glucose
  8. 8. Disorders inMitochondrial Hepatopathy1. Fatty Acid Oxidation Defects 2. Respiratory Chain Defects
  9. 9. “The Masquerader Of All Diseases” Highly Deceptive !
  10. 10. Why do we struggleto identify this disease ? Mitochondrial Diseases
  11. 11. Settings to predict this disease
  12. 12. Settings in GI practice
  13. 13. 107 patients FAOD 74% 30% 31% 13% 16% 10%<1mo 1mo – 1yr 1yr – 2 yr >2yr unknown 36% 40% 8% 12% 0.01% 82% N= 50 Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
  14. 14. 24%8% FAOD & RCD - Clinical features8%3%8%8%20% Lee ,Sokol Semin Liver Dis5% 2007;27:259–273.
  15. 15. Saudubray et al, J. Inher. Metab. Dis. 1999 (22) 488-502
  16. 16. FAOD ImportanceShort Chain  Not much of a problemDoes it really exist??  Developmental delay  Behavioural problemsMedium Chain (80%)  Good prognosis(1:15,000 new born screen)  Maximum heterogeneity  Mortality: 16-25%  Intellectual delay 20-25%  <6yr : decompensation  >6yr : death risk reducedLong Chain  Mainly liver manifestations(1:85,000 new born screen)  Adverse prognosisPrimary Carnitine deficiency  Early presentation and death(1:750,000 - 2,000,000) J Inherit Metab Dis (2010) 33:501–506
  17. 17. Long Chain Hydroxy Acyl CoA Dehydrogenase Def. (LCHADD) Early onset: severe Hypertrophic cardiomyopathy phenotype Pericardial effusion Lethality 40-80% May have HE Neonatal CholestasisInfantile onset: hepatic Hepatomegaly, steatosis phenotype (steatosis) HypoglycemiaLate onset: myopathic Exercise induced rhabdomyolysis phenotype (CK: 200,000 u/l: acute 500-5000 u/l
  18. 18. Very Long and Long ChainHydroxy Acyl CoA Dehydrogenase Def. (VLCHADD and LCHADD) J Inherit Metab Dis (2010) 33:501–506
  19. 19. Biochemical differentiation Acidosis Urine Blood sugar Serum Serum ketones Lactate AmmoniaFAOD ++ Nil Low + + (non-ketotic hypoglycemia)RCD ++ ++ Normal ++++ ±OA +++ ++/+++ Low/ Normal/ Normal ++ (persistent) HighUCD Normal ++++
  20. 20. Fatty Acid Oxidation Defects Screening Definitive (available in India) (NOT available) Tandem MS: Quantitative Fatty acid analysis C8-10 in MCAD C14-18 in LCHAD Enzyme activity in C14 in VLCAD cultured skin fibroblasts or muscle + Plasma carnitine and acylcarnitine assay biopsy •Very low levels reaching zero: Carnitine def. also primary carnitine def •25-50% reduction: Other FAODGCMS: Urinary organic acid and acylglycine assay (available) - dicarboxyllic acids
  21. 21. Respiratory Chain Defects involving Liver Disorder Onset Disorder OnsetNeonatal Liver Acute Pearsons synd Insidious failure Villous atrophy syndrome ChronicMitochondrial AcuteDNA depletion Navajo Acute / Alpers synd Insidious Neurohepatopathy chronic
  22. 22. Respiratory Chain Defects involving LiverNeonate Infancy Childhood Adult
  23. 23. Respiratory Chain Defects
  24. 24. Definitive Sample Availability Tests in India Ragged red fiber Muscle Yes (Histology) Analysis of oxygen Liver, muscles, fibroblasts Noconsumption Polarographic fresh biopsy specimens studies required (5-10gm) Enzymatic activity of Frozen samples No respiratory chain (liver, kidney, myocardium) complexes larger tissue (open surgical in most centers) Mt DNA deletions and Muscle No mutations
  25. 25. Treatment Lee ,Sokol Semin Liver Dis 2007;27:259–273
  26. 26. Role of Carnitine Lee ,Sokol Semin Liver Dis 2007;27:259–273

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